Natural killer (NK) cells kill tumors, reject B2-microglobulin-deficient bone marrow, and participate in host defense against pathogens. In many of these functions, the Syk tyrosine kinase is implicated in NK cell activation. However, this has not bee evaluate in Syk-deficient NK cells and the role of Syk in NK cells activities in vivo has not been evaluated. Unfortunately, Syk-deficient mice die in the perinatal period, before NK cells develop. This subproject will be directed by Dr. Yokoyama and take advantage of the collective expertise of Drs. Chan, Cheng, Dustin, and Waksman to definitely evaluate the role of Syk in NK cell functions in vitro and in vivo. In particular, the subproject will utilize hematopoietic sem cell from Syk-deficient and Syk-mutant produced or proposed by Dr. Cheng to reconstitute a mouse with a selective deficiency in NK cells produced by Dr. Yokoyama. This system will address the following specific aims: 1) Evaluate the role of Syk in NK cell development in vivo; 2) Determine the role of Syk in NK cell activities in vitro and in vivo; 3) Analyze Syk-dependent signaling in NK cells; and 4) Evaluate the mechanisms of Syk function in NK cells. Therefore, this project will provide a comprehensive yet focused analysis of the contribution of Syk to NK cell activities.